Cannabis use is very prevalent especially in adolescence. Its widespread use is partially related to the concept of being somewhat harmless as compared to other drugs of abuse. Yet cannabis has been shown to induce dependence, sensitization or tolerance to other drugs, psychosis, anxiety, depression and cognitive disturbances. Clinical and preclinical data suggest that its use in adolescence may have long lasting effects on the brain and may affect dopaminergic transmission. Despite much clinical and preclinical data to this effect no imaging studies of dopamine transmission in cannabis users are available to date. Forty non treatment seeking cannabis dependent subjects (CD) and 40 matched healthy controls (HC) will undergo PET scanning with the D2/3 receptor radiotracer [11 C] raclopride at baseline and after administration of 0.3 mg/kg d-amphetamine (i.v. bolus). We will measure in the baseline scan [11 C] raclopride binding potential (BP), and the specific-to-nonspecific equilibrium partition coefficient (V3"), both measures of receptor availability, in the striatum as a whole and in striatal substructures. On scans 2 we will measure the change in V3" compared to baseline, AV3", related to amphetamine induced DA release. We predict that similarly to other substances, cannabis dependence will be associated with low striatal D2 (SA1) and low ventrostriatal stimulated dopamine release (SA2). This study will provide for the first time information on the effects of chronic cannabis use on the dopaminergic related reward circuits in the brains of human subjects and will allow drawing comparisons between cannabis, a drug thought to be harmless, and other drugs such as cocaine or alcohol. This is likely to have a significant impact on public health and psychiatry. In a companion grant we will propose later to investigate the same parameters in dual diagnosis (comorbid schizophrenia and cannabis dependence) patients as dopaminergic systems may be differentially affected in the mesolimbic versus associative corticostriato-thalamo-cortical loops by these two conditions. [unreadable] [unreadable] [unreadable]